Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
Copyright policy )Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble Aβ. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.
- University of South Florida United States
- Florida Southern College United States
- James A. Haley Veterans' Hospital United States
- National Institute of Health Pakistan
- Saitama Medical University Japan
Mice, Inbred C3H, Amyloid beta-Peptides, Amino Acid Motifs, Mice, Transgenic, Cell Line, Mice, Inbred C57BL, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Animals, Aspartic Acid Endopeptidases, Humans, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational
Mice, Inbred C3H, Amyloid beta-Peptides, Amino Acid Motifs, Mice, Transgenic, Cell Line, Mice, Inbred C57BL, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Animals, Aspartic Acid Endopeptidases, Humans, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational
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